Autonomous, ambulatory analyte monitor or drug delivery device

ABSTRACT

The invention relates to analyte monitoring/drug (pharmaceutical agent) delivery device. The invention is suited for monitoring various blood constituents such as glucose. The device has a housing that at least partially encloses a plurality of microneedles disposed on a carrier and an electronics portion. Each microneedle is in fluid communication with a corresponding microchannel. Each microneedle is individually addressable. That is, each microneedle can be extended and retracted individually via an actuator. The electronics portion includes a processor and associated circuitry (e.g., memory, supporting electronics and the like), a motor or the like, a sensor, a power supply (e.g., battery) and optionally an interface. In general, the processor controls the operation of the device and is data communication with the actuator, motor, sensor and interface. The invention provides for autonomous operation, that is, without intervention of the user. The invention can optionally provide for calibration without intervention of the user. The invention can also provide for semi-continuous monitoring for day and night time. The invention can provide for up to four, or more, weeks of operation. The invention can provide for a device that is relative small in size, and therefore unobtrusive. The invention can also provide for device with remote control and interactive electronics. The invention may be also used for the delivery of various pharmaceutical agents including high potency drugs to minimize patient intervention and minimize discomfort.

This application claims the benefit of Provisional Patent ApplicationSer. No. 60/355,195, fled Feb. 8, 2002.

The invention relates to the field of analyte monitoring and/or drug(pharmaceutical agent) delivery devices and in particular relates to ananalyte monitoring, or drug delivery device that provides for ambulatoryoperation.

Home analyte monitoring is most widely used to monitor glucose by thosewho have diabetes mellitus. In the most serious form of diabetesmellitus, Type 1 or insulin dependent diabetes mellitus (IDDM), thepancreas fails to produce insulin. For those who have Type 1 diabetes,glucose levels must be frequently monitored in order to provide, byinjection, the appropriate amount of insulin. The widespread use of homeglucose monitoring reflects the fact that clinical trials have shownthat frequent glucose monitoring, and good insulin maintenance,significantly reduces the loss of quality of life, and correspondingcost of care, associated with diabetes mellitus. There is a need forfrequent and accurate self-testing of glucose. However, the discomfort(pain) from use of lancets and the need for manipulation of lancets,strips and hand-held monitors, often in public, significantly reduce thefrequency of self-testing for glucose.

United States Patent Application No. 2002/0006355 discloses a test stripfor use in the determination of the concentration of a chemical inblood. The test strip has a plurality of microneedles in fluidcommunication with a common test area. The microneedles are adapted topuncture skin and to draw blood. The test area contains a reagentadapted to produce a reaction indicative of the concentration of thechemical in blood.

However, in operation, the user is required to initiate a blood glucosemeasurement by pressing the microneedle patch onto the user's skin. Eachof the microneedles lances the skin. A quantity of blood is moved bycapillary action from the collection point of each microneedle to thetest area. The glucose in the blood reacts with a reagent incorporatedinto the test chamber producing a signal indicative of the blood glucoseconcentration. That signal is then measured by the user with anappropriate sensor in a blood glucose analyzer (e.g., a handheld device)to determine the concentration of glucose in the user's blood. Once theblood glucose analyzer measures the signal produced by the reaction, thetest strip (and microneedle patch) is discarded. Improvements in thefield of analyte monitoring and/or drug delivery devices are needed.

Moreover, in the area of drug delivery, the biotechnology industry hasproduced important therapeutics which have unique drug delivery issues.Currently protein and peptide therapeutics are almost exclusivelydelivered by injection. The parenteral route, although an effectivemeans of delivery is often viewed as complex and inconvenient to thepatient. There is no better example of this that the delivery ofinsulin.

Accordingly, the invention relates to an analyte monitoring/drug(pharmaceutical agent) delivery device. The invention is suited formonitoring various blood constituents such as glucose. The device has ahousing that at least partially encloses a plurality of microneedlesdisposed on a carrier and an electronics portion. Each microneedle is influid communication with a corresponding microchannel. Each microneedleis individually addressable. That is, each microneedle can be extendedand retracted individually via an actuator. The electronics portionincludes a processor and associated circuitry (e.g., memory, supportingelectronics and the like), a motor or the like, a sensor, a power supply(e.g., battery) and optionally an interface.

In general, the processor controls the operation of the device and isdata communication with the actuator, motor, sensor and interface. Theinvention provides for autonomous operation, that is, withoutintervention of the user. The invention can optionally provide forcalibration without intervention of the user. The invention can alsoprovide for semi-continuous monitoring for day and night time. Theinvention can provide for up to four, or more, weeks of operation. Theinvention can provide for a device that is relative small in size, andtherefore unobtrusive. The invention can also provide for device withremote control and interactive electronics. The invention may be alsoused for the delivery of various pharmaceutical agents including highpotency drugs to minimize patient intervention and minimize discomfort.

SUMMARY OF THE INVENTION

The invention relates to an analyte monitoring device operable to draw afluid sample from a subject. The device has a first plurality ofmicroneedles and a plurality of monitoring microchannels. Each of thefirst plurality of microneedles is at least intermittently in fluidcommunication with a corresponding monitoring microchannel. Eachmonitoring microchannel is also associated with a reagent. The devicehas at least one actuator operable to extend each microneedle to drawthe fluid sample from the subject. The device also has a controlleroperable to initiate analyte testing of the fluid sample.

In a preferred aspect of the invention the actuator is operable toextend at least one of the first plurality of microneedlesomnidirectionally. In another preferred aspect of the invention each ofthe first plurality of microneedles has an internal diameter in therange of about 25 to 200 micrometers. In another preferred aspect of theinvention each of the first plurality of microneedles is fabricated fromat least one of metal, plastic, glass and crystal. In another preferredaspect of the invention each of the first plurality of microneedles hasa distal end that is operable to penetrate into a skin surface to amaximum of about 2.5 mm.

Preferably, the fluid sample is substantially blood. In anotherpreferred aspect of the invention each of the first plurality ofmicroneedles is at least intermittently in fluid communication with amonitoring microchannel via a conduit. In another preferred aspect ofthe invention each monitoring microchannel is operable to store thefluid sample and accumulation of the fluid sample in the monitoringmicrochannel is entirely dependent on capillary forces.

In another preferred aspect of the invention each of the monitoringmicrochannels has at least one internal surface that is at leastpartially coated with at least one insoluble material to enhance thecapillary forces and minimize coagulation. In another preferred aspectof the invention the plurality of monitoring microchannels arefabricated in an array. In another preferred aspect of the invention themonitoring microchannels are fabricated in an array having approximately50-150 microchannels formed in a maximum diameter of approximately 5 cm.In another preferred aspect of the invention each of the first pluralityof microneedles is dimensioned for volumes of fluid in the range ofabout 50-500 nanoliters.

The device can be provided with a detector operable to determine whenthe fluid sample completely fills at least one monitoring microchannelsuch that the accumulation of the fluid sample with the associatedmicroneedle may be terminated. In another preferred aspect of theinvention at least one monitoring microchannel is in fluid communicationwith at least one reagent operable to assay for analytes selected fromthe group of (a) glucose, (b) cholesterol, (c) ethanol, (d) digoxin, (e)HDL cholesterol, (f) lithium, (g) sodium, (h) phenytoin, (i)therophylline, (j) cyclosporine, (k) cancer chemotherapy drugs, (l) DNA,(m) RNA, (n) extended phenytonin sodium, (o) warfarin sodium, and (p)proteins derived from blood.

Optionally, at least two monitoring microchannels are associated with asingle microneedle so that multiple assays can be performed using asingle microneedle. In another preferred aspect of the invention asecond plurality of microneedles and a plurality of calibrationmicrochannels filled with calibration fluid, wherein at least one assayis initiated for calibration purposes.

Optionally, the device can include a third plurality of microneedles anda plurality of pharmaceutical agent delivery microchannels wherein eachpharmaceutical agent delivery microchannel is at least partially filledwith a pharmaceutical agent. In another preferred aspect of theinvention at least one monitoring microchannel is sealed with a polymer.

In another preferred aspect of the invention the controller is operableto initiate analyte testing based on a time schedule. In anotherpreferred aspect of the invention the controller is operable to adjustthe analyte testing time schedule.

In another preferred aspect of the invention the controller is operableto couple to a portable computing device. In another preferred aspect ofthe invention the portable computing device is a PDA. In anotherpreferred aspect of the invention the controller and the portablecomputing device is operable to select or modify times for analytetesting.

In another preferred aspect of the invention the plurality ofmicroneedles and plurality of monitoring microchannels are disposable.In another preferred aspect of the invention the controller and theactuator are reusable. In another preferred aspect of the invention theplurality of microneedles, plurality of monitoring microchannels,actuator and controller are portable.

The device can also include a heating source operable to heat at leastone injection site prior to extending a microneedle. In anotherpreferred aspect of the invention the heating source is an opticalheating source.

The device can include a housing at least partially coated with anadhesive operable to attach the housing to a surface, wherein thehousing at least partially enclosing the plurality of microneedles andthe monitoring microchannels. In another preferred aspect of theinvention the device includes a generally disc shaped housing at leastpartially enclosing the plurality of microneedles and the monitoringmicrochannels.

The invention is also directed to a pharmaceutical agent delivery deviceoperable to deliver a pharmaceutical agent to a subject. The device hasa first plurality of microneedles and a plurality of pharmaceuticalagent delivery microchannels. Each of the first plurality ofmicroneedles is at least intermittently in fluid communication with acorresponding pharmaceutical agent delivery microchannel. Eachpharmaceutical agent delivery microchannel is at least partially filledwith a pharmaceutical agent. The device has at least one actuatoroperable to extend each microneedle to deliver the pharmaceutical agentto the subject, and. The device also has a controller operable toinitiate delivery of the pharmaceutical agent.

In a preferred aspect of the invention the actuator is operable toextend at least one of the first plurality of microneedlesomnidirectionally. In another preferred aspect of the invention each ofthe first plurality of microneedles has an internal diameter in therange of about 25 to 200 micrometers. In another preferred aspect of theinvention each of the first plurality of microneedles is fabricated fromat least one of metal, plastic, glass and crystal. In another preferredaspect of the invention each of the first plurality of microneedles hasa distal end that is operable to penetrate into a skin surface to amaximum of about 2.5 mm.

Preferably, the fluid sample is substantially blood. In anotherpreferred aspect of the invention each of the first plurality ofmicroneedles is at least intermittently in fluid communication with apharmaceutical agent delivery microchannel via a conduit. In anotherpreferred aspect of the invention the delivery of the at least onepharmaceutical agent delivery is at least partially dependent onhydraulic forces, preferred aspect of the invention the plurality ofpharmaceutical agent delivery microchannels are fabricated in an array,preferred aspect of the invention the pharmaceutical agent deliverymicrochannels are fabricated in an array having approximately 50-150microchannels formed in a maximum diameter of approximately 5 cm,preferred aspect of the invention each of the first plurality ofmicroneedles is dimensioned for volumes of fluid in the range of about50-500 nanoliters.

The device can include a detector operable to determine when thepharmaceutical agent delivery microchannel is empty. The device can alsoinclude a third plurality of microneedles and a plurality of monitoringmicrochannels wherein each monitoring microchannel is associated with areagent. Preferably, at least one pharmaceutical agent deliverymicrochannel is sealed with a polymer.

In another preferred aspect of the invention the controller is operableto initiate pharmaceutical agent delivery based on a time schedule. Inanother preferred aspect of the invention the controller is operable toadjust the pharmaceutical agent delivery time schedule.

In another preferred aspect of the invention the controller is operableto couple to a portable computing device. In another preferred aspect ofthe invention the portable computing device is a PDA. In anotherpreferred aspect of the invention one of the controller and the portablecomputing device is operable to select or modify times for analytetesting.

In another preferred aspect of the invention the plurality ofmicroneedles and plurality of pharmaceutical agent deliverymicrochannels are disposable. In another preferred aspect of theinvention the controller and the actuator are reusable. In anotherpreferred aspect of the invention the plurality of microneedles,plurality of pharmaceutical agent delivery microchannels, actuator andcontroller are portable.

The device can include a heating source operable to heat at least oneinjection site prior to extending a microneedle. In another preferredaspect of the invention the heating source is an optical heating source.

The device can also include a housing at least partially coated with anadhesive operable to attach the housing to a surface, wherein thehousing at least partially enclosing the plurality of microneedles andthe pharmaceutical agent delivery microchannels. The device can alsoinclude a generally disc shaped housing at least partially enclosing theplurality of microneedles and the pharmaceutical agent deliverymicrochannels.

The invention is also directed to the combination of a device having ananalyte monitor portion operable to draw a fluid sample from a subjectand a pharmaceutical agent delivery portion operable to deliver apharmaceutical agent to the subject. The device has a first plurality ofmicroneedles and a plurality of monitoring microchannels. Each of thefirst plurality of microneedles is at least intermittently in fluidcommunication with a corresponding monitoring microchannel. Eachmonitoring microchannel is associated with a reagent. The device alsohas a second plurality of microneedles and a plurality of pharmaceuticalagent delivery microchannels. Each of the second plurality ofmicroneedles is at least intermittently in fluid communication with acorresponding pharmaceutical agent delivery microchannel. Eachpharmaceutical agent delivery microchannel is at least partially filledwith a pharmaceutical agent. The device has at least one actuatoroperable to extend each microneedle to either draw the fluid sample fromthe subject or deliver the pharmaceutical agent to the subject. Thedevice also has a controller operable to initiate analyte testing of thefluid sample and delivery of the pharmaceutical agent.

The device can also include a third plurality of microneedles and aplurality of calibration microchannels filled with calibration fluid,wherein at least one assay is initiated for calibration purposes.

The invention it also directed to a method for automated analytemonitoring. The method includes providing a first plurality ofmicroneedles and a plurality of monitoring microchannels. Each of thefirst plurality of microneedles is at least intermittently in fluidcommunication with a monitoring microchannel. Each monitoringmicrochannel is associated with a reagent. The method includessequentially extending a microneedle thereby obtaining a fluid samplefrom a subject and then initiating analyte testing of the fluid sample.A controller is provided to automatically repeat the sampling andtesting steps.

The invention is also directed to a method for automated pharmaceuticalagent delivery. The method includes providing a first plurality ofmicroneedles and providing a plurality of pharmaceutical agent deliverymicrochannels. Each of the first plurality of microneedles is at leastintermittently in fluid communication with a correspondingpharmaceutical agent delivery microchannel. Each pharmaceutical agentdelivery microchannel is at least partially filled with a pharmaceuticalagent. The method includes extending a microneedle thereby deliveringthe pharmaceutical agent to a subject. A controller is provided toautomatically repeat the pharmaceutical agent delivery step.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a pictorial view of a portion of an analyte monitoring/drugdelivery device in accordance with the invention.

FIG. 2 is a pictorial view showing additional structural details of thecarrier microneedles, microchannels and conduit in accordance with FIG.1.

FIG. 3 is a pictorial view showing additional structural details of thecarrier microneedles, microchannels and conduit in accordance with FIGS.1 and 2.

FIG. 4 shows an alternate embodiment of an analyte monitoring/drugdelivery device in accordance with the invention.

FIG. 5 shows another alternate embodiment of an analyte monitoring/drugdelivery device similar to the device shown in FIG. 4 also incorporatinga fluidic capture and processing site in accordance with the invention.

FIG. 6 is a pictorial view showing additional details of the embodimentshown in FIG. 5 in accordance with the invention.

FIG. 7 is a pictorial view showing additional details of the embodimentshown in FIGS. 5 and 6 in accordance with the invention.

FIG. 8 is a pictorial view showing additional details of the embodimentshown in FIGS. 5-7 in accordance with the invention.

FIG. 9 shows another alternate embodiment of an analyte monitoring/drugdelivery device in accordance with the invention.

FIG. 10 is a pictorial diagram showing a lead-screw drive mechanism formicroneedle motion in accordance with the invention.

FIG. 11 is a pictorial diagram showing a straight microneedle withorthogonal entry in accordance with the invention.

FIG. 12 is a pictorial diagram showing a curved microneedle withorthogonal entry shown in three sequential positions in accordance withthe invention.

FIG. 13 is a pictorial diagram showing a straight microneedle withangled entry shown in three sequential positions in accordance with theinvention.

FIG. 14 is a pictorial diagram showing a curved microneedle with angledentry shown in three sequential positions in accordance with theinvention.

FIG. 15 is a pictorial diagram showing a straight microneedle with anon-rectilinear motion shown in four sequential positions in accordancewith the invention.

FIG. 16 is a pictorial diagram showing the basic configuration forimproved sensitivity in accordance with the invention.

FIGS. 17a and 17b are pictorial diagrams showing an exemplaryconfiguration for enhanced light collection using a spherical mirror toimprove sensitivity in accordance with the invention.

FIGS. 18a and 18b are pictorial diagrams showing another exemplaryconfiguration for enhanced light collection using a lenses and/or aprism to improve sensitivity in accordance with the invention.

FIGS. 19a and 19b are pictorial diagrams showing yet another exemplaryconfiguration for enhanced light collection using a lenses and/or aprism to improve sensitivity in accordance with the invention.

FIG. 20a is a pictorial diagram showing enhanced blood collection bylocalized heating of capillary structures (blood) near puncture site inaccordance with the invention.

FIG. 20b is a pictorial diagram showing an alternative structure forenhanced blood collection by localized heating of capillary structures(blood) near puncture site in accordance with the invention

FIG. 21 is a block diagram showing a feedback loop from blood sensor tocontrol logic to control the depth of microneedle penetration inaccordance with the invention.

FIG. 22 is a pictorial diagram showing force applied to the proximal endof a microneedle to cause the distal portion to project into multipledirections in accordance with the invention.

FIG. 23 is a graph showing the error in the volume of a 1 cm length of anominal 88 micrometer tube by increased tube diameter.

FIG. 24 is a pictorial diagram showing an exemplary PDA display showingtest times in accordance with the invention.

FIG. 25 is a pictorial diagram showing an exemplary PDA display showingdietary recommendations in accordance with the invention.

FIG. 26 is a pictorial diagram showing how data is entered into aRecommender System in accordance with the invention.

FIG. 27 is a pictorial diagram showing an exemplary PDA, Disposable andReusable module in accordance with the invention.

FIG. 28 is a pictorial diagram showing exemplary locations on the bodyfor placement of a device in accordance with the invention.

FIGS. 29a-29c are pictorial diagrams showing an exemplary embodimentsuitable for location on the wrist.

FIGS. 30a-30b are pictorial diagrams showing an exemplary embodimentsuitable for location on the waist.

FIGS. 31a-31b are pictorial diagrams showing an exemplary embodimentsuitable for location on the arm.

FIGS. 32a-32b are pictorial diagrams showing an exemplary embodimentsuitable for adhesive mounting in a variety of locations including theleg.

FIGS. 33a-33c are pictorial diagrams showing an exemplary embodimentsuitable for strap mounting a device in accordance with the invention tothe leg.

FIGS. 34a-34c are pictorial diagrams showing an exemplary embodimentsuitable for clip and/or adhesive mounting a device in accordance withthe invention to the waist via an undergarment.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 shows a pictorial diagram of a portion of a analytemonitoring/drug (pharmaceutical agent) delivery device 10 in accordancewith the invention. The device has a housing (lower portion only shown)12 that at least partially encloses a plurality of microneedles 14disposed on a carrier 16 and an electronics portion 18. The carrier 16,as shown in FIG. 1, is generally a planar substrate having a circularprofile. It is understood that the carrier 16 can be formed with varietyof different geometric shapes without departing from the invention.

A plurality of microchannels 20 are disposed on the carrier 16. Eachmicroneedle 14 is in fluid communication with at least one microchannel20. FIG. 1 shows an embodiment in which each microneedle 14 is in fluidcommunication with a single microchannel 20. Each microneedle 14 isindividually addressable. That is, each microneedle 14 can be extendedand retracted individually via an actuator. A variety of actuators arecompatible with the invention.

FIG. 1 shows an embodiment in which each microneedle 14 can be extendedand retracted via an actuator (a portion of which is not shown)including an arm 22 having a proximal end 24 supported by a hub 26located generally in the center of the carrier 16. The arm 22 also has adistal end 28 that is generally disposed above a single microneedle 14.

The device also includes an electronics portion 18 having a processor 30and associated circuitry (e.g., memory, supporting electronics and thelike), a motor 32 or the like, a sensor 34, a power supply (e.g.,battery) 36 and optionally an interface 38. In general, the processor 30controls the operation of the device and is in data communication withthe actuator, motor 32, sensor 34 and interface 38. Operation of theprocessor 30 and associated software is discussed in more detail below.

In the embodiment shown in FIG. 1, carrier 16 is movable so that eachmicroneedle 14 is individually addressable (i.e., can be extended andretracted individually). The carrier 16 is rotatably mounted via hub 26and is generally driven by motor 32. The connection between motor 32 andthe carrier 16 can be accomplished via gears, belts and the like asdiscussed in more detail below. The interconnection of movable carriersand drive mechanisms suitable for use in conjunction with the inventionbased on the disclosure herein is well within the scope of one skilledin the art.

FIG. 2 shows some of the structural details of the carrier 16 shown inFIG. 1. The carrier 16 has a plurality of microneedles disposedgenerally adjacent to an edge 40. Microneedle 14′ is shown in theextended position (the actuator is not shown). Each microneedle 14generally has an internal bore in fluid communication with amicrochannel 20 via a conduit 42. FIGS. 1 and 2 show microchannels thatare generally disposed along a radial line extending between the hub 26(disposed on a central axis) and the associated microneedle. Themicrochannels are generally shown in a nested configuration (i.e., tworows). This configuration is advantageous since it allows formicrochannels that are generally wider than the microneedles andprovides for increased microneedle density (i.e., more closely spacedmicroneedles) at the peripheral edge 40 of the carrier 16. It isunderstood that microchannels 20 can be positioned in a variety ofgeometric configurations without departing from the scope of theinvention. It is also understood that conduits 42 can be routed in avariety of geometric configurations as necessary to link with themicrochannels 20.

FIG. 3 shows additional structural details of the carrier 16,microneedles 14, microchannels 20 and conduits 42 generally inaccordance with FIGS. 1 and 2. Microchannel 20 is preferably providedwith a cover 88. Preferably the cover is at least partially translucentor transparent to facilitate optical detection of assays. The covergenerally protects the contents of the microchannel from contamination.The cover can be generally rigid or flexible as discussed in more detailbelow.

Each microneedle 14 is formed with a proximal end 44 that interfaceswith the microchannel 20, and a distal end 46 operable to penetrate thetissue or skin (for collecting a sample of blood or delivering a drug orpharmaceutical agent). The proximal end 44 is formed with an opening 48that generally couples to the conduit 42.

In operation, a single microneedle 14 is moved into the extendedposition and penetrates the skin. Opening 48 is aligned with conduit 42coupling the microneedle 14 with the microchannel 20 in fluidcommunication. The device is generally operable to function as a monitorand collect a sample of blood to be analyzed. The device is alsooperable to deliver a drug or pharmaceutical agent. Each microneedle 14can be designated for monitoring or drug delivery. For monitoring,microneedle 14 is preferably associated with a “monitoring microchannel”configured for a specific assay technique (e.g., having a reactionlayer) as discussed in more detail below. For drug delivery, microneedle14 is preferably associated with a “pharmaceutical agent deliverymicrochannel” that is at least partially filled with the drug orpharmaceutical agent to be delivered as discussed in more detail below.

FIG. 4 shows an alternate embodiment of a device. In this embodiment,the plurality of microneedles 114 and the carrier (not shown) aregenerally stationary with respect to the housing (not shown). Themicrochannels are not shown although the location and interconnection ofmicrochannels for use in conjunction with this embodiment of theinvention based on the disclosure herein is well within the scope of oneskilled in the art.

Each microneedle 114 has a proximal end 144 extending towards a centralaxis 178 and distal end 146 directed downward (i.e., directed at theskin or tissue). The proximal end 144 of each microneedle 114 ispreferably anchored or coupled to the carrier. Each microneedle 114generally includes a curve or bend 176 thereby defining a ramp portion160 formed between the proximal and distal ends. In this embodiment, theanchored proximal end 144 and ramp portion provide an incline used toextend the microneedle 114 as well as a spring biasing of themicroneedle in the retracted position. Other arrangements for springbiasing the microneedle are readily apparent to those skilled in theart.

The actuator includes a cam 162, a track 164 formed with slots 166 and aslider 168 having an index pin 170. The actuator also includes a motor(not shown) or the like for driving or rotating the cam about thecentral axis 178. The connection between such a motor and the cam 162can be accomplished via gears, belts and the like as discussed in moredetail below. The interconnection of cam and drive mechanisms suitablefor use in conjunction with the invention based an the disclosure hereinis well within the scope of one skilled in the art.

The slider 168 is movable between a retracted position (closer to thecentral axis) and an extended position (further from the central axis).In the retracted position, the slider is disposed generally above theramp portion 160 of at least one microneedle 114 and preferably does notcontact the microneedle. The slider is also preferably biased or springloaded in the retracted position. Biasing mechanism or springs are notshown. However, the biasing mechanisms or spring loading of a slider foruse in conjunction with the invention based on the disclosure herein iswell within the scope of one skilled in the art. The slider shown inFIG. 4 is generally shown between the retracted and extended position.

As cam 162 rotates, it pushes the slider 168 outward along the track164. The slider has a lower portion 172 operable to contact a singlemicroneedle 114 as the slider moves from the retracted position to theextended position. The index pin 170 is slidably engaged in slots 166,thereby restricting the slider to motion along a linear path (along theramp portion 160 of a single microneedle 114). As the slider moves alongthe ramp portion 160, the distal end 146 of the microneedle 114 isforced downward (e.g., into the tissue for collecting a sample ordelivering a pharmaceutical agent). Once the cam reaches its maximumlobe height 174, the slider 168 returns to the retracted positionallowing microneedle 114 to respond to spring biasing forces andwithdraw from the tissue.

The track 164 generally has a proximal end 165 that is pivotally engagedalong the central axis. Once the slider 168 returns to the retractedposition allowing microneedle 114 to spring out of the tissue, track 164is then advanced (i.e., rotated clockwise or counter-clockwise) to indexor address to the next microneedle 114. The cycle can then be repeated.

It is understood that microneedles 114 do not have to be continuous instructure. For example, a fluidic capture and processing site can belocated at the bend 176 of each microneedle 144. This site can interfacewith a fluidic layer positioned below the microneedles. When themicroneedle is fully depressed, it preferably aligns with the fluidicprocessing layer forming a continuous fluid path. This path preferablyremains sealed until the microneedle 114 is pressed down.

FIG. 5 shows another alternative embodiment of a device incorporating afluidic capture and processing site as discussed above. In thisembodiment, the plurality of microneedles 214 and the carrier 216 aregenerally stationary with respect to the housing (not shown). Eachmicroneedle 214 has a distal end 246 directed downward (i.e., directedat the skin or tissue) and a proximal end 244 engaged in fluidic capturesite 280. A spring member 261 is coupled between the fluidic capturesite 280 and the carrier 216 thereby defining a spring biased rampportion 260.

The actuator includes a cam 262 having a tooth 284, a track 264 formedwith at least one slot 266 and a slider 268 having an index pin 270. Theactuator also includes a ring gear 282 that is coupled to housing (notshown) and is generally stationary with respect to the track 264. Asdiscussed above, the track 264 is pivotable around the central axis 278.The actuator also includes an idler gear 286 that driven by the tooth284 as discussed in more detail below. Idler gear 286 has a pivot pointthat is anchored to the track 264, and generally moves the track in anincremental fashion, to index or address successive microneedles 214.

The slider 268 is movable between a retracted position (closer to thecentral axis) and an extended position (further from the central axis).In the retracted position, the slider is disposed generally above theramp portion 260 of at least one microneedle 214 and preferably does notcontact the microneedle. The slider is also preferably biased or springloaded in the retracted position. Biasing mechanism or springs are notshown. However, the biasing mechanisms or spring loading of a slider foruse in conjunction with the invention based on the disclosure herein iswell within the scope of one skilled in the art. The slider shown inFIG. 5 is generally shown in the retracted position. Microneedles 214′and 214″ are shown in an intermediate position and the extendedpositions respectively for illustrative purposes only.

As cam 262 rotates (clockwise), it pushes the slider 268 outward alongthe track 264. The slider has a lower portion operable to contact asingle microneedle 214 as the slider moves from the retracted positionto the extended position. The index pin 270 is slidably engaged in slot266, thereby restricting the slider to motion along a linear path (alongthe ramp portion 260 of a single microneedle 214). As the slider movesalong the ramp portion 260, the distal end 246 of the microneedle 214 isforced downward (e.g., into the tissue for collecting a sample ordelivering a pharmaceutical agent).

Once the cam reaches its maximum lobe height, the slider 268 returns tothe retracted position allowing microneedle 214 to spring out of thetissue. Tooth 284 engages the idler gear 286 and advances the gear byone tooth. Track 264 is then advanced (i.e., rotated counter-clockwise)to index or address to the next microneedle 214. The number of teeth onidler gear 286 and ring gear 282 are selected so that each single toothmovement of the idler gear 286 results in the proper angulardisplacement of the track 264 to precisely index or address the nextmicroneedle 214. The cycle can then be repeated.

FIGS. 6-8 are pictorial views showing additional details of theembodiment shown in FIG. 5. Continuing with the discussion above, oncemicroneedle 214 is in the extended position, the proximal end of themicroneedle 244 and fluidic capture site 280 interfaces with amicrochannel 220. The fluidic capture site is formed with an openingthat generally couples to a conduit 234 and ultimately microchannel 220as discussed with respect to FIG. 3.

In a monitoring configuration, depression of microneedle 214 results inthe collection of blood in microchannel 220. Microchannel 220 ispreferably configured for a specific assay technique (e.g., having areaction layer) as discussed in more detail below. The reaction ispreferably monitored by sensor 234 mounted to the 268 slider generallydisposed above microchannel 220.

Microchannel 220 is preferably provided with at least some form ofcover. Preferably the cover is at least partially translucent ortransparent to facilitate optical detection of assays. See e.g., cover88 in FIG. 3. The cover generally protects the contents of themicrochannel from contamination. The cover can be generally rigid orflexible. For delivery of a drug or pharmaceutical agent, the drug ispreferably fluid is stored in a compressible microchannel (e.g., amicrochannel having a flexible cover). As the slider 268 moves towardsthe extended position it preferably presses the microneedle 214 into theskin or tissue. As the microneedle is inserted the slider can at leastpartially compressing microchannel 220 and forcing the fluid out throughthe conduit 242 and ultimately the microneedle 214 and into the skin ortissue. It is understood that both monitoring and drug delivery becarried out within the same device by allocating a portion ofmicroneedles 214 for each task.

It is also understood that other mechanisms can be used to facilitatedelivery of pharmaceutical agents. For example, a small fluidic pump canprovide positive pressure to the microchannel. The pharmaceutical agentcontained in the microchannel is then expelled through the through themicroneedle. Optionally, a capacitance detector can be used to sensethat the microchannel is empty and can signal that the fluidic pumpshould be turned off, thereby controlling the possibility of airentering the delivery system.

FIG. 9 shows another alternative embodiment of a device 310 inaccordance with the invention. The device has a housing (only partiallyshown) 312 that at least partially encloses a plurality of microneedles314 disposed on a carrier 316. The carrier 316 is generally a planarsubstrate having a ring-like profile. It is understood that the carrier16 can be formed with variety of different geometric shapes withoutdeparting from the invention.

A plurality of microchannels 320 are disposed on the carrier 316. Inthis embodiment, the 388 cover is arranged on an inside edge 340 of thesubstrate 316. Each microneedle 314 is preferably in fluid communicationwith a single microchannel 320. Each microneedle 314 is individuallyaddressable.

FIG. 9 shows an embodiment that is somewhat similar to FIG. 1 in thateach microneedle can be extended and retracted via an actuator (aportion of which is not shown) including an arm 322 having a proximalend supported by a hub 326 located generally in the center of thedevice. The arm 322 also has a distal end 328 that is generally disposedabove a single microneedle 314.

The device also includes an electronics portion having a processor 330and associated circuitry (e.g., memory, supporting electronics and thelike), a motor or the like (not shown), a sensor 334, a power supply orbattery (not shown) and optionally an interface (not shown).

In the embodiment shown in FIG. 9, the plurality of microneedles 414 andthe carrier 316 are generally stationary with respect to the housing312. The connection between the drive motors and the arm 322 is notshown. This can be accomplished via gears, belts and the like asdiscussed above. The interconnection of the microchannels 320,microneedles 414, conduits, drive mechanisms and the like in conjunctionwith the invention based on the disclosure herein is well within thescope of one skilled in the art.

Exemplary System Segmentation

Three exemplary system modules have been identified to optimally meetthe requirements of a user friendly, diagnostically relevant, and lowcost analyte monitoring/drug (pharmaceutical agent) delivery system. Theanalyte monitoring/drug (pharmaceutical agent) delivery system, ispreferably partitioned into a Disposable Module, a Reusable Module and aPDA Module. See e.g., FIG. 27. This configuration optimally distributesfunctionality amongst these three configurations to achieve certainadvantages. However the invention is not limited to this configuration.For example, a one-unit disposable device including all electronics,microneedles, chemistry, mechanics and user interface may bealternatively employed. Or, more relevantly, the design of the inventionallows for any distribution of components between one or more systemmodules. For example, components may be partitioned among one or moresystem modules based on the overall system cost, user safety and/orperformance concerns.

The Disposable Module—

This module contains those components that once used must be discardedto maintain biological safety and diagnostic accuracy. This modulepreferably includes any structural or mechanical elements to maintainintegrity, sterility and an electromechanical interface to any reusablecomponents. Therefore this system module preferably includes:microneedles, a microfluidic assembly, membrane, reagent chemistry andassociate housing materials. This module can also include retainingmechanisms for establishing and maintaining intimate contact with thebody thereby providing mechanical retention of the analytemonitoring/drug (pharmaceutical agent) delivery system.

The Reusable Module—

This module preferably contains those components that control, automatemotion, measure the glucose reaction, alarm the user, transmit data tothe PDA module. This module can also include retaining mechanisms forestablishing and maintaining intimate contact with the body therebyproviding mechanical retention for the analyte monitoring/drug(pharmaceutical agent) delivery system. Preferably, this moduleincludes: a microprocessor with associated circuitry (e.g., memory,supporting electronics and the like), a sensor (e.g., an electro-opticalsensor) for evaluating the products of any reactions (e.g., glucosereactions), drive mechanisms such as motors or the like, a sensor, apower supply (e.g., battery) 36 and an interface operable to communicatewith a portable computing device or PDA. The interface can be RF,magnetic or inductive, optical or the like. Using magnetic or inductivecoupling rather than RF coupling is advantageous since it canpotentially avoid FCC restrictions or limitations. The reusable modulecan also an audible or vibration alarm to notify the user that useraction intervention is required.

The PDA Module—

This module preferably includes a separate user interface via a portablecomputing device such as a personal digital assistant (PDA), handheldcomputer or the like for controlling and/or interacting with the device.A typical portable computing device includes a processor, memory,associated circuitry, a display (e.g., monochrome or color LCD) and aninput device such as a key pad, touch screen (e.g., integrated with thedisplay) or the like and an operating system. Previously availableglucose monitors were specifically designed for handling the paper teststrips, for viewing numerical values of the glucose measurements and forsetting other parameters of the meter such as its calibration. Thesecustom designed units had limited functionality and relatively crudeuser interfaces.

Today, portable computing devices with improved operating systemsoftware and user interfaces are readily available. These devicesprovide the potential for richer and extended functionality. For examplea typical PDA includes a relatively large viewing screen (important tothe many diabetic elderly) and can also include wireless communicationsmechanisms, a sophisticated operating system and a variety of businessand personal software (calendars, scheduling, etc.). Accordingly, a PDAprovides a robust platform for developing diabetic related software.Recently the FDA approved the first PDA for monitoring EKG activity. Theinvention preferably includes the use of a PDA to provide theproprietary software (programs) for autonomous operation with animproved user interface.

To this end, the PDA module preferably provides the user with softwarethat facilitates informed decisions to help the diabetic user moreoptimally adjust either drug or dietary consumption to more optimallycontrol glucose. The PDA configuration provides a user interface andpreferably allows users the ability to program and or control testing.The user can view individual glucose measurements and graphicallydisplay glucose value trends by the day, week or custom time period. ThePDA can be used to display any and all of the measurements recorded bythe system. Using the proper software, the user can be provided withrecommendations for drug regiment modification (insulin or other). Theuser can also be provided with recommendations for dietary changes. SeeFIG. 25. The PDA can also store grocery lists for daily menus. Thegrocery list can be viewed by the user as needed to ensure properdietary intake.

The user can preferably program the times when their analyte tests areto be taken. Preferably, the user can also set the upper and lowerlimits for alerts. As shown, a graphic showing a clock can be easilyused to select or modify times for testing. See FIG. 24.

Whenever the user makes changes and with verification from the user, theinformation is wirelessly downloaded to the system. During the day theuser will not need to use the PDA unless alerted by the system to checkfor an analyte reading. The user can initiate a test from the PDA ifwanting to make an immediate measurement. Once the user selects thiscommand, verifies it, and transmits it to the Reusable, a confirmationis made back to the PDA.

An increased number of tests per day can be accommodated for a shorteruse life. For example, a newly diagnosed diabetic can have a 24 test perday regiment for the first 6 days to ascertain maximum peaks and lowswith various daily regiments of exercise, stress and food types. Thenwith the user profiled, the caregiver may reduce the number of tests toan appropriate level. Additional aspects of the PDA module andassociated software is discussed below.

Exemplary Microneedle Structures

The invention encompasses mechanisms operable to extend a microneedlethat is smaller than most used today for injection or blood extraction(referred to herein as a microneedle). The use of microneedles allowsfor the extraction of blood with minimal discomfort or pain. It has beennoted that blood extraction by the mosquito is efficient. This insecthas managed to do what man cannot, that is, to extract blood essentiallywithout pain while drawing blood through a micrometer hollow member.

The mosquito accomplishes blood extraction by use of a proboscis whichconsists of two tubes surrounded by two pairs of cutting stylets thatare together in a tight bundle. This bundled entity is called thefascicle and the bundle is about 40 to 60 micrometers in diameter. Thefascicle breaks the skin surface of the victim with its stylets. Oncebelow the surface, the fascicle bends at a sharp angle to beginexploring for blood. With each insertion, the mosquito attempts to hit avenule or arteriole. On each try, the mosquito will withdraw thefascicle slightly while leaving it in the original hole, and angle it ina different direction. Once blood is found, the mosquito may draw bloodfor about ninety seconds and will draw a few micrograms, e.g., 5microliters, of blood. The invention encompasses technology that mimicsthe function of the mosquito and within the disclosed analytemonitor/drug delivery system.

The diameter of a microneedle is, for example, optimally about 40 to 120micrometers, approximately the size of the mosquito's proboscis.Preferably, the microneedle is driven into the skin or tissue to a depthto yield a sample that is mostly blood with minimal interstitial fluid.The microneedle preferably has an internal diameter of about 25 to 100micrometers, sufficient for blood to flow freely and, preferably, toflow by capillary action. Needles of this type have been demonstrated byKumetrix, Inc. (e.g., a MEMS based silicon microneedle having aninternal microfluidic channel approximately 25 micrometers in width,providing very strong capillary forces but allowing the erythrocytes toflow without difficulty).

The invention is alternatively operable with standard hypodermic tubingrather than silicon MEMS microneedles (e.g., to achieve sufficientstrength at low cost). Hypodermic tubing is currently available in sizesdown to 75 micrometers in diameter. Alternatively the microneedles canbe made from glass and drawn to thin diameters similar to the way hollowcapillary tubing is drawn. It is understood that microneedles suitablefor use in conjunction with the invention can be fabricated by a varietyof methods. It is also understood that microneedles suitable for use inconjunction with the invention can be fabricated from a variety ofmaterials including, but not limited to, metal, plastic, glass andcrystal (e.g., quartz).

The microneedle can be either straight or curved and enter the skinrectilinearly, curvilinear or obliquely. Orthogonal entry withrectilinear motion is potentially the simplest to achieve,advantageously requiring a minimal length of tubing below the epidermis.See FIG. 11. A potential disadvantage is that the minimum length mayfail to erupt or puncture enough blood vessels to cause blood to flow insufficient volume. Entering the skin obliquely increases the number ofpotential blood vessels skewered but may aggravate more nerve endings.Making the microneedle curved also tends to access more tissue and canenhance collection by crossing more blood vessels without penetratingdeeply. The orthogonal method will be optimal where blood is acquiredreadily and where nerve ending are rich. The oblique or curvedmicroneedle approach is optimal where nerve fibers are less dense.

As an alternative to a straight microneedle having an orthogonal entry,a curved microneedle can be used with orthogonal entry. See FIG. 12. Inthe alternative, a straight microneedle can be used with angled entry.See FIG. 13. In the alternative, a curved microneedle can be used withrotational entry. See FIG. 14. In the alternative, a straightmicroneedle can be used with a non-rectilinear motion. See FIG. 15. Thealternate approach shown in FIG. 15 utilizes motion that does not matchthe shape of the microneedle. This results in the microneedlepenetrating one layer of tissue with minimum disruption while producingmore disruption at other depths. This effect can be used to minimizepain while still disrupting enough blood vessels to enable sufficientsample collection. FIG. 15 shows a straight microneedle with circularmotion, steps 1 to 4, where the center of the motion is well above thesurface of the skin. Other motion forms are anticipated includingcomplex forms.

The microneedle is preferably extended and retracted mechanically.Microneedle extension and retraction can be powered by a single deviceor a combination of devices. For example, a DC motor can be used todrive an extending means and a spring can provide the return force.Alternatively, a powered source such as a DC motor can both drive themicroneedle into and out from the skin. The later is a preferredapproach in that it provides optimal control over the microneedleposition.

The additional advantage of the articulated microneedle drive is that itmimics the exploratory motion of the mosquito. The microneedle can bedriven to a maximal depth in one area and then, without removing it fromthe skin, reciprocate the microneedle and cause it to move in a newdirection. In order to cause a new direction at a remote point on apenetrating microneedle, a stress must be imposed on the microneedleexternal to the skin while the distal end of the microneedle is still inthe skin. See FIG. 22.

It is understood that various techniques can be used to drive themicroneedles in accordance with the invention. Aside from the techniquesdiscussed above, extending and retracting the microneedle can beaccomplished using a micro-miniature DC motor and associated gear train.See e.g., FIG. 10. In this embodiment rotational output of the motor(not shown) is transferred through a gear train 492 to an internallythreaded gear 494 located above the microneedle 414. The rotation of thegear causes a ‘leadscrew’ 490 to move linearly to gear rotation. Thusthe motor causes a drive to extend or retract the microneedle 414. Thisdesign can achieve the penetration forces necessary, a value that isdependent on skin type, thickness and physical microneedle parameters,typically in the range of 0.01 to 0.07 Newtons.

The lead screw drive mechanism is preferably driven by a captured nutforcing the screw to travel co-linear with the intended microneedletravel. The lead screw engages with the microneedle assembly, pushes themicroneedle into the tissue, pulls the microneedle out and disengagesfrom coupling 496. The drive mechanism preferably pivots to engage thenext microneedle assembly. The nut can be driven by gears as shown inFIG. 10, or a belt or other motion transfer mechanisms. The back end ofthe microneedle can be accessed by various techniques including but notlimited to an opening in the engagement mechanism, an opening in themicroneedle side or a bend in the microneedle exposing the proximalopening. Incorporation of a leadscrew mechanism suitable for use inconjunction with the invention based on the disclosure herein is wellwithin the scope of one skilled in the art.

Other motion generating sources or motion conveyance can alternativelybe used. For example, the motor can drive a cam device with featuresthat cause the microneedle to extend downward with a predetermined rateprofile. Cam features, or springs, can be used to retract themicroneedle. Also, a shape memory alloy material (SMA) can be used tocause the microneedle to extend down and back. The heating and coolingof the SMA can cause the appropriate amount of force and displacement. Asolenoid type device can be used to either drive the microneedledirectly or index the microneedle. Such a device can be used like amotor.

Having articulated motion allows the microneedle to be extended into theskin incrementally to the correct depth. This invention is suitable foruse on skin surfaces where a relatively flat surface is available equalto or larger than the a real dimension of a wrist. Although, theinvention can be configured to acquire blood from more curving surfacessuch as a finger. The invention is preferably configured to acquireblood from specific places such as the upper arm, wrist, abdomen, back,thigh or lower leg. The invention can be disposed or worn beneathclothing to render it inconspicuous.

Exemplary device configurations for differing body locations arediscussed in more detail below. Depending on the location selected, thethickness of the skin surface and depth to the capillary bed isvariable. For example, the epidermis varies in thickness from 0.02 mm atthe eyelids to 1.4 mm on the soles of the feet. The dermis likewisevaries from 0.6 to 2.5 mm. The invention is preferably configured tohave a distal end of the microneedle reside into the vascular plexus butnot go to a depth sufficient to penetrate the deep dermal vascularplexus. Accordingly, the invention preferably operates over a range ofabout 1.0 to 2.0-mm penetration into the skin surface.

Exemplary Sensor Structures

Various sensor structures are compatible with the invention. Forexample, optical detection can be achieved by techniques such ascolorimetry and fluorescence. FIG. 16 shows basic configuration having amicrochannel 520 and a reaction layer 521 in fluid communication with amicroneedle 514. The reaction layer can be a membrane that is coatedwith a chemically active components that provide a change in color inthe presence of the desired analyte (e.g., glucose) for colorimetricmeasurements. A fluid sample is collected via microneedle 514 and isstored in microchannel 520. The appropriate reagent is preferablycontained within the microchannel 520 so that a reaction is initiatedupon collection of the fluid sample. The sensor is disposed generallyabove the microchannel 520 and has an emitter 535 operable to illuminatethe reaction layer with an appropriate frequency of light. The sensoralso has a detector 537 operable to detect light reflected off of thereaction layer as shown by arrows 539. The detector 537 can beimplemented using a photodiode with single or multiple picture elements(pixels). The example of such a device is a CMOS or CCD imager. Theemitter and detector are preferably controlled by the processor (notshown). The detector output is preferable read by the processor and isfurther processed in order to determine the results of the reaction.FIGS. 17a and 17b show an enhanced collection configuration to improvesensitivity. This sensor configuration includes a spherical mirror 541for reflecting light from one or more emitter 535 to the detector 537.

FIGS. 18a and 18b show alternative sensor configurations. FIG. 18a showsa microchannel 520 and a reaction layer 521 in fluid communication witha microneedle 514. Also shown in FIG. 18a is a cover 588 as discussedabove. The reaction layer 521 can be a membrane or porous media that iscoated with a chemically active component that changes color in thepresence of the desired analyte (e.g., glucose) for colorimetricmeasurements. A fluid sample is collected via microneedle 514 and isstored in microchannel 520. The appropriate reagent is preferablycontained within the microchannel 520 so that a reaction is initiatedupon collection of the fluid sample. The sensor is disposed generallyabove the microchannel 520 and has an emitter 535 operable to illuminatethe reaction layer with the appropriate frequency of light. The sensoralso has a detector 537 operable to detect light reflected off of thereaction layer 521. Lenses 543 are disposed between the between theemitter 535 and the reaction layer 521 as well as between the detector537 and the reaction layer 521. Lenses 535 generally focus the light forimproved illumination of the reaction layer 521 and light collection atthe detector 537. FIG. 18b is similar to FIG. 18a but includes acoupling prism 589 disposed on the cover to improve performance of thedetector.

FIGS. 19a and 19b show further alternative sensor configurations. FIG.19a shows a microchannel 520 and a reaction layer 523 in fluidcommunication with a microneedle 514. Also shown in FIG. 19a is a cover588 as discussed above. The reaction layer 523 is shown as a generallythin layer having assay reagents mixed in a support matrix applied tothe microchannel 520. A fluid sample is collected via microneedle 514and is stored in microchannel 520. The appropriate reagent is preferablycontained within the microchannel 520 so that a reaction is initiatedupon collection of the fluid sample. The sensor is disposed generallyabove the microchannel 520 and has an emitter 535 operable to illuminatethe reaction layer with the appropriate frequency of light. The sensoralso has a detector 537 operable to detect light reflected off of thereaction layer 523. Lenses 543 are disposed between the between theemitter 535 and the reaction layer 523 as well as between the detector537 and the reaction layer 523. Lenses 535 generally focus the light forimproved illumination of the reaction layer 523 and light collection atthe detector 537. FIG. 19b is similar to FIG. 18a but includes acoupling prism 589 disposed on the cover to improve performance of thedetector. It is understood that the microchannel cover 588 can beenhanced with a variety of optical properties such as lenses, filters,reflective structures, refractive structures and the like withoutdeparting from the invention.

Enhanced Blood Collection

The invention also encompasses various techniques for enhanced bloodcollection. FIGS. 20a and 20b show the use of heating sources (e.g.,infrared emitting LED) to heat the tissue near the collection site.Heating the capillary structure of the tissue at the collection site canlead to improve the blood supply and enhanced collection usingmicroneedles. FIG. 20a shows an exemplary microneedle 514 inserted inskin or tissue. Heating source 598 is located to one side of themicroneedle and is directed towards the tissue thereby heating thetissue in which the microneedle is inserted. FIG. 20b shows an alternateembodiment in which the heating source 599 is generally ring shaped andis located coaxially around the microneedle 514.

Automatic Detection of Blood

To simplify the acquisition of blood and to assure that an adequatesample is taken this invention encompasses the use of a blood detectionsensor. The blood detection sensor provides control over the penetrationand extraction control. The sensor feedback loop works by incrementallydriving the microneedle into the skin, waiting an appropriate time forblood to fill the microneedle and sensor and then retracting themicroneedle. See FIG. 21. If no blood is detected within a reasonableperiod of time, then the motor can further drive the microneedle to agreater depth. When blood has been acquired the microneedle isretracted.

The blood-sensor can be located at various points along the blood path(e.g., microneedle, microfluidic channel, microfluidic well or at thereaction site) of the test device or preferably, the test means itselfis the sensor. The optical sensor for the colorimetric test can detectthe appearance of blood, prior to making a reading to ascertain theglucose level. This provides dual function of the sensing device andprovides a feedback loop without additional cost. Alternatively, acapacitance, conduction or resistive sensor can be used in themicrofluidic channel or well to determine when liquid is present.

Since the depth and rate at which blood is acquired are site, user andtime specific there is need to have these variables stored in thesystem. Since it is envisioned that this device be used with a cartridgecontaining a multiplicity of microneedles, and since each bloodacquisition is a repetitive search and detect methodology, it is helpfulto the user if the system could optimize itself to achieve minimal bloodacquisition time.

Analyte Testing and Delivery of Pharmaceutical Agents

Since 1987, the American Diabetes Association (ADA) has providedcriteria for the statistical assessment of self-monitoring blood glucose(SMBG) meters. In 1987, the ADA recommended blood glucose measurementsshould be within 15% of the reference and that future SMBG meters shouldhave less than 10% variability. By 1993, it was evident newtechnologies, at this time, were not achieving the 1987 goals. However,in 1996, the ADA recommended less than 5% variability for future SMBGmeters.

In comparison to this standard, recent evaluation of the relativeaccuracy of selected, available SMBG meters, representing visual,colorimetric and amperometric detection, showed that current productsvary from a reference by approximately −5 to +20%. The significance ofstatistical errors for SMBG meters depends on clinical assessment, thatis, whether the error results in inappropriate clinical management.

Recognizing that SMBG meters using relatively large microliter volumesof blood show large statistical errors. The invention contemplates theuse of small (e.g., nanoliter) volumes for samples. This helps toachieve the small size of the device necessary for ambulatorymonitoring. The requirement of new design and precision manufacturingapproaches, as noted, are the subject of this invention, i.e., toachieving better accuracy. The invention contemplates the use of small(e.g., nanoliter) volumes for samples. In addition to achieving betteraccuracy, this also helps to achieve the small size of the devicenecessary for ambulatory monitoring. The requirement of new design andprecision manufacturing approaches, as noted, are the subject of thisinvention.

In order to support small volume fluid assays, the inventionincorporates microfluidic channels with a reagent membrane for aplurality of blood analyte testing. FIG. 3 shows an exemplary array ofmicrochannels 20 each with precise dimensions, that is, micrometerdimension tolerances. A membrane can be bonded onto the array to preventthe migration of red blood cells, but not liquid blood constituents. Theunbonded side of the membrane is preferably coated with assay reagentseither uniformly or in spatial defined locations, that is, the channellocations. When blood enters an individual microchannel, the dimensionof the microchannel determines the volume. This is critical to theprecision of the assay, that is, filling the microchannel provides theanalytical volume for assay. Subsequent to filling, the bloodconstituents migrate through the “reaction layer” (e.g., a polymer) andinitiate, by wetting, the assay chemistries within the reaction layer asdiscussed herein.

The polymer for the reaction layer, may be any commercial polymersuitable for the desired assay whereby, by wetting, the assaychemistries may be initiated within or on the other side of the polymerlayer. Preferred polymers include hydroxyethyl cellulose, sodiumalginate and gelatin. The reaction layer is preferably cast on polymerssuch as styrene or any polymer of high liquid transmittance andcapability for sealing. The polymer and reaction layer is preferablysealed to the capillary well using a device with precision dimensions tosurface bond the polymer and reaction layer using adhesive bonding byheat, adhesive materials or other means or agents.

The need for precision in the dimension of the device is evident fromFIG. 23. This figure shows the error in the volume of a 1 cm length of anominal 88 micrometer tube when the tube diameter is increased (e.g., a5% error occurs with a nominal 91 micrometer diameter tube). It can beseen that a change in diameter of less than 3 micrometers in a nominal88 micrometer diameter tube can result in an approximately 5% error involume. Accordingly, the tolerance required to control volume to lessthan 5% is on the order of <3 micrometers.

The assay chemistries can be based on widely used techniques such as theTrinder reaction. The Trinder reaction is based on a coupling reactionbetween two dye precursos, viz.,

beta-D-glucose+0₂+H₂0=D-gluconic acid+H₂0₂  (1)

2H₂0₂+4-aminoantipyrine+1,7-dihydroxynaphthalene=red dye  (2)

in the presence of glucose oxidase for the first reaction and in thepresence of a peroxidase for the second reaction. The Trinder reactionis widely used for glucose assays. The important features of the Trinderreaction are the long history of use, the stability of the dyeprecursors with elevated temperatures and the availability, and thermalstability, of the enzymes. The 1,7-dihydroxynaphthalene is soluble onlyin alcohol and a water soluble aromatic is preferred. This aromatic ispreferably one of the water soluble reagents identified in U.S. Pat. No.4,350,762—DeLuca, et al., for example, the sodium salt of2,4-dichlorophenyl sulphonate.

The specific configuration of the invention differs from priortechnology in a number of ways including but not limited to the examplesdiscussed below. The invention incorporates micromachined, ormicromolded, microchannels with precise dimensions, that is, micrometerdimension tolerances. The accumulation or delivery of fluid (e.g.,blood, pharmaceutical agent . . . ) is direct, that is from amicroneedle. The accumulation of fluid in the microchannel is entirelydependent on capillary forces. The microchannel surfaces may be thinlycoated with insoluble materials, such as various polymers, to enhancethe capillary forces and minimize blood coagulation. The microchannelscan be fabricated as an array in large number, e.g., 150 on a 1.5″diameter. The microchannels can be dimensioned for minimal fluid volumes(e.g., 100-500 nanoliters of fluid or less).

The microchannels can be provided with a mechanism to detect when thefluid completely fills the device such that use of the associatedmicroneedle can be terminated (i.e., the microneedle can be retracted),as discussed below. The microchannels and assay chemistries may beapplied to assays for analytes other than glucose. The invention can bemodified to provide multiple channels for multiple assays using a singleblood sample. So called “calibration microchannels” may be initiallyfilled with calibration fluid and the assay initiated for calibrationpurposes as discussed in more detail below. This aspect of the inventioncan only be realized with the structures disclosed herein as discussedin more detail below. The microchannels may be filled with drug and usedto deliver drugs used in small doses (high potency). The capability todeliver drug and or monitor blood analytes in an automated fashion usinga portable device can only be realized with the structures disclosedherein.

Ultimately, the invention encompasses the combination of both themonitoring and pharmaceutical agent delivery system within one unit(preferably a disposable unit). For example, military personnel may beunknowingly exposed to a toxin. The device can periodically extractblood and assay for predetermined toxins. If a toxin is detected, thedevice can deliver antidote.

Self Calibration

In order to increase the accuracy of an enzymatic test, it has beenfound helpful in current SMBG meters to provide, with each batch of teststrips, a calibration factor that is a correction factor to be used tomore accurately determine the correct result. Two calibrations areneeded—one to compensate for instrument components and secondly tocompensate for the particular sensitivity of a specific batch ofchemical components. Various techniques have been developed to achievethis in an automated fashion.

The invention preferably incorporates autonomous self-calibrationfunctions so that no user actions are required. One or more calibrationmicroneedles (i.e., associated with a calibration microchannels) arepreferably incorporated in the microfluidic structure. When thecalibration microneedle is actuated, it is pushed down but nomicroneedle extends from the disposable unit. In the fully extendedposition, the unit releases a calibration fluid into the microfluidicchannel. For example, in the extended position the calibration fluidtravels through the conduit and fills the microchannel. The assay systemprovides a measure of the glucose in the calibration solution andcompares this measure value with the known value. Preferably, acorrection factor is derived from the calibration process. Thecorrection factor is preferably stored electronically and is utilizedduring subsequent analyte testing.

A plurality of calibration microneedles can be used to compensate forany change in reagent or instrument properties. Thus the firstmeasurement taken with the insertion of a new Disposable is to calibratethe meter. Subsequent measures are made on a timed basis and are used bythe system software to compensate for change in reagent properties atroom temperature.

Testing for Other than Glucose

The invention can be utilized to test for a variety of constituentsincluding but not limited to enzymes, antibodies, alcohol level andother blood constituents. The invention can be designed to alsoincorporate HbAlc (glycosylated hemoglobin) blood testing, which is atest diabetics should have done about twice a year or more and providesa measure of long term effectiveness in regulating blood glucose levels.Virtually any blood test that has chemistries that can be used at ornear body temperature can be incorporated within this system. It is alsoenvisioned that the invention can provide Polymerase Chain Reaction(PCR) testing to genetically identify foreign bodies within the blood. Arelatively small heating element can be provided for resting thatutilizes heat melts of duplex nucleic acid. Insulation can also beprovided to minimize any heating of surrounding structure.

4. Alternate Assay Technologies

A review of the literature shows, by select examples, that a variety ofcolorimetric, electrochemical and fluorescent assay methods areavailable. Of these methods, U.S. Pat. No. 6,118,126—Zanzucchi disclosesfluorescence assay techniques and this technology may be used as analternate method of assay for the device of this invention. Thistechnology allows for the enhancement of fluorescence from texturedsurfaces. In connection with the invention, enhanced fluorescence canprovide improved sensitivity for the assay of small samples. It isunderstood that a variety of other assay techniques can be used withoutdeparting from the scope of the invention.

Use of a Neural Network to Optimize the Acquisition of Blood

In order to make the system more user friendly, a simple learningalgorithm, using artificial intelligence (AI) schemes such as neuralnetworks, can be used by the system's computer. The algorithm can inferfrom historical data of multiple blood acquisitions the parameters thatare specific to an individual. These additional variables can be;location on the body, time from last meal, time since last exercise andtime of day (capillaries are more blood rich during the day andparticularly during times of physical activity). These data can then beused to infer the probability of blood acquisition and therefore theoptimal microneedle depth and dwell time.

Since physical activity is closely related to the metabolism of glucosein the body, this invention also encompasses the inclusion of anaccelerometer within the ambulatory device. Both the accumulative motionand time since last physical activity can provide critical data toassist in the predictive ability. Software, such as the “Recommender”may also be included in this invention. See FIG. 26. This software canprovide the user better recommendations as to how to control theirglucose with drug or dietary regiments, e.g., in the case of type 2, ornoninsulin dependent, diabetes.

The invention is preferably operable to be linked to an externalcomputing device such as a PDA. Preferably, the PDA can also store inmemory the schedule of the person as additional information with respectto activity. This additional information may be used with the softwareto anticipate fluctuations of glucose in the user and to supportrecommendations on diabetes control.

Drug Modification

One of the major reasons for noncompliance is that there is not a tightfeedback loop between the glucose measurement and compensatory actions.The invention can provide not only a reading of glucose level butrecommendations for more or less insulin, or oral medication ornutritional supplements.

Often critical is insulin use. All people with Type 1 diabetes need touse it. Many people with type 2 or gestational diabetes also use insulinfor good control. For Type 1 diabetics taking insulin injections, theneed is to inject the appropriate mix of rapid or short acting insulin(lispro) and intermediate or long acting insulin (Lente or Ultralente).ADA recommends about four injections a day. If on an insulin pump, theneed is to achieve a basal delivery to maintain fasting glucose levelsand anticipate the need for bolus injections before meals. The inventioncan be coupled to either regiment and make the decision and estimatingprocess easier.

Diet and Nutrition Modification

Automated diabetes management software has previously been developed toassist diabetics to control blood glucose levels—most have failed due tothe complexity of the model and the unmet need for more glucosereadings. Diabetic management software attempts to recommend changes toa diabetic's drug dosage or dietary regiment to minimize the occurrenceof hyperglycemic or hypoglycemic events. These systems require extensivehistorical and real time data to accurately predict how an individual'sblood glucose will behave with some level of intervention.Unfortunately, these systems have failed because user's behavior andphysiological response is too unpredictable—only short term predictionsbased on real time blood glucose measurements can be used to help modifyoutcome.

FIG. 25 shows an exemplary PDA display showing dietary recommendations.FIG. 26 shows pictorially how data are typically entered into aRecommender System. Since mathematical modeling of any biological systembecomes difficult due to the numerous metabolic mechanisms, researcheshave investigated the use of artificial intelligence (AI) includingneural networks, fuzzy logic and expert systems.

Incorporation of as Alarm in the System

Since the invention is to be worn in a discrete place, it would beinconvenient for the user to have to physically or visually access itwhile wearing it to determine a glucose measure. It should also not benecessary for the user to be constantly interrogating the PDA todetermine if the user's glucose is exceeding a predefine level, or hasgone below a lower predefined level. It is more convenient, ergonomicand socially acceptable to use a wireless personal digital assistant,such as that produced by Palm or Handspring, that is modified tocommunicate directly with the Reusable unit.

Therefore it is envisioned with this invention that the wearablecomponent or Reusable include an alarm to alert the user that theirglucose reading is outside some predefined range. The alarm can be ofthe audible or vibration mode as commonly found in pager type devices.The invention is to the software to monitor the data and provide thealarm.

Timing System to Allow Flexible Predefined Testing Times

A timing system is preferably incorporated in the system software toprovide for a flexible testing schedule. As discussed above, the usercan program the times when their glucose test are to be taken and forsetting the upper and lower limits for alerting the user. Whenever theuser makes changes and with verification from the user, the informationis preferably wirelessly downloaded to the system. During the day theuser will not need to use the PDA unless alerted by the system to checkfor a glucose reading. The user can initiate a test from the PDA ifwanting to make an immediate measurement. Once the user selects thiscommand, verifies it, and transmits it to the Reusable, a confirmationis made back to the PDA.

Alternative Forms for Locating the Device on the Body

The invention includes the ability to locate the device at variousregions on the body. FIG. 28 is a pictorial diagram showing exemplarylocations on the body for placement of a device in accordance with theinvention.

FIGS. 29a-29c are pictorial diagrams showing an exemplary embodimentsuitable for location on the wrist. This configuration includes a strapoptionally containing a battery that binds the disposable/reusablemodule to the wrist similar to a wrist watch.

FIGS. 30a-30b are pictorial diagrams showing an exemplary embodimentsuitable for location on the waist. This configuration includes amounting housing with associated straps operable to hold thedisposable/reusable module against the waist. FIGS. 31a-31b arepictorial diagrams showing an exemplary embodiment suitable for locationon the arm. This configuration includes an arm band optionally fittedwith book and loop fasteners for attaching to the arm similar to a bloodpressure cuff.

FIGS. 32a-32b are pictorial diagrams showing an exemplary embodimentsuitable for adhesive mounting in a variety of locations including theleg. This configuration includes an adhesive backed disk that covers thedisposable/reusable module, holding against the skin. FIGS. 33a-33c arepictorial diagrams showing an exemplary embodiment suitable for strapmounting a device in accordance with the invention to the leg. Thisconfiguration includes a mounting housing with associated strapsoperable to hold the disposable/reusable module against the leg.

FIGS. 34a-34c are pictorial diagrams showing an exemplary embodimentsuitable for clip and/or adhesive mounting a device in accordance withthe invention to the waist via an undergarment. This configurationincludes a mounting housing operable to hold disposable/reusable moduleand formed with a spring joint similar to a clothes pin. Thedisposable/reusable module is at least partially covered with anadhesive. The spring joint is placed over the edge of an undergarmentand the adhesive is pressed against the skin (e.g. along the waist). Itis understood that various other configurations are possible withoutdeparting from the scope of the invention.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein.

1-59. (canceled) 60: A method of diabetes management comprising:instructing a user to follow an initial glucose concentration testingregimen via a user interface of a portable computing device, wherein theinitial testing regimen has a first number of glucose concentrationtests; generating, using the portable computing device, a user profilefrom test results of the initial glucose concentration testing regimen;and after generating the user profile, instructing a user via the userinterface to decrease a number of glucose concentration tests performedbelow the first number of glucose concentration tests. 61: The method ofclaim 60, wherein at least one of a user's exercise data and a user'sfood data is also used to generate the user profile. 62: The method ofclaim 61, wherein both a user's exercise data and a user's food data arealso used to generate the user profile. 63: The method of claim 62,wherein a user's stress data is also used to generate the user profile.64: The method of claim 60, wherein the portable computing device is ahandheld computer. 65: The method of claim 60 further comprisingwirelessly receiving the test results of the initial glucoseconcentration testing regimen from an analyte monitoring deviceconfigured to measure a glucose reaction. 66: The method of claim 65,wherein the analyte monitoring device comprises a reusable module and adisposable module. 67: The method of claim 66, wherein the disposablemodule comprises a carrier containing a plurality of microneedles. 68:The method of claim 60 further comprising recommending, via the userinterface, a drug regimen modification. 69: The method of claim 68,wherein the drug is insulin. 70: The method of claim 60 furthercomprising recommending, via the user interface, a dietary change. 71:The method of claim 60 further comprising displaying an individualglucose concentration test result on the user interface. 72: The methodof claim 60 further comprising graphically displaying trends from thetest results of the initial glucose concentration testing regimen on theuser interface. 73: The method of claim 60 further comprising alerting auser when a glucose concentration test result is outside a predefinedrange. 74: The method of claim 60 further comprising alerting a userwhen a glucose concentration test result is above an upper limit orbelow a lower limit. 75: The method of claim 60 further comprisingalerting a user to check a glucose concentration test result via theuser interface. 76: The method of claim 60, wherein the portablecomputing device is a glucose monitor comprising at least onemicroneedle. 77: A device for diabetes management comprising: a userinterface; and a processor configured to: instruct a user to follow aninitial glucose concentration testing regimen via the user interface,wherein the initial testing regimen has a first number of glucoseconcentration tests; generate a user profile from test results of theinitial glucose concentration testing regimen; and after generation ofthe user profile, instruct the user via the user interface to decrease anumber of glucose concentration tests performed below the first numberof glucose concentration tests. 78: The device of claim 77, wherein atleast one of a user's exercise data and a user's food data is also usedto generate the user profile. 79: The device of claim 78, wherein bothof a user's exercise data and a user's food data are also used togenerate the user profile. 80: The device of claim 79, wherein a user'sstress data is also used to generate the user profile. 81: The device ofclaim 77, wherein the processor is further configured to wirelesslyreceive the test results of the initial glucose concentration testingregimen. 82: The device of claim 77, wherein the processor is furtherconfigured to recommend a drug modification via the user interface. 83:The device of claim 82, wherein the drug is insulin. 84: The device ofclaim 77, wherein the processor is further configured to recommend adietary change via the user interface. 85: The device of claim 77,wherein the processor is further configured to display an individualglucose concentration test result on the user interface. 86: The deviceof claim 77, wherein the processor is further configured to graphicallydisplay trends from the test results of the initial glucoseconcentration testing regimen on the user interface. 87: The device ofclaim 77, wherein the processor is further configured to alert a user,via the user interface, to check a glucose concentration test result.